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1. Field of the Invention
The present invention relates to acne and other inflammatory skin diseases. More particularly, the present invention relates to methods of treating acne and other inflammatory skin diseases including, but are not limited to, acne vulgaris, acne rosacea, acne conglobata, sebaceous cysts and hidrandenitis suppurativa through the oral administration of at least one drug selected from the group consisting of anti-leukotriene agents, and anti-histamine agents. These include, but not limited to, leukotriene antagonists, blockers, and inhibitors, as well as histamine antagonists, blockers, and inhibitors.
2. General Background of the Invention
Acne vulgaris is a dermatological disorder that affects 17 million Americans with a prevalence rate exceeding 85% in teenagers, declining to about 8% in 25 to 34 year olds, and to 3% in 35 to 44 year olds8. It is multifactorial and its course varies with cause and age. xe2x80x9cThere is no disease that produces more psychic trauma, maladjustment, insecurity, and feelings of inferiority than does acne.xe2x80x9d13 
For many family physicians acne vulgaris is a very complex and challenging illness due to its inconsistent and often mutable response to treatment. All too many physicians are aware of the insidious nature of this disease and the intense emotional or physical disturbance resulting from acne. No other malady has as its consequence such intense feelings of inferiority, maladjustment and insecurity. The majority of cases seen in the outpatient clinical arena are those that have either been previous treatment failures or those that are presenting for re-treatment because of ongoing medical noncompliance. Often patients are disinclined to continue a chronic, multi-drug treatment regimen because of the potential for developing undesirable side effects, notwithstanding, the assumption of burdensome medical risks. Avoidance of treatment measures usually results in predictable exacerbations of acne lesions and a depreciative outcome, whereas treatment tolerance and potential adversity is rewarded with success.
Recently several authors have reviewed and summarized the treatment options for acne vulgaris.8, 10 Although effective treatment is available for both short and long term management of acne vulgaris, a strategy for oversight and individualization is essential as relapse is not uncommon; nonetheless, satisfactory results are not guaranteed with the use of any one of the currently available drugs alone. Although the medical causes of acne vulgaris are not known, most patients can be managed with a variety of drugs that have been developed recently. However, results vary based on one""s particular choice of chemotherapy or method of medical management. Although many effective pharmaceutical preparations, both prescription and nonprescription, are currently available for use in the treatment of acne vulgaris, no one drug appears effective against all distinctive types of acne and most preparations are laden with significant side effects. Comedolytic agents, for example, in their attempt to promote comedonal drainage cause significant skin irritation. Topical antibiotics decrease the number of mild to moderate inflammatory lesions by inhibiting the growth of p. acnes and are also associated with skin irritation, dryness, and potential antibiotic resistance. Oral antibiotics are the standard for treating moderate to severe acne lesions, however, superinfection may occur and long-term use requires routine laboratory monitoring. Hormones in their attempt to decrease sebum production are not without side effects and are usually reserved for females. Oral Vitamin A acid derivatives, although very effective, are only approved for severe nodular acne and commonly exhibit serious adverse reactions.8 
Anti-infectious agents, have also been used as a treatment for acne and other inflammatory skin diseases. Although used quite often in family practice and other medical settings, anti-infectious agents at doses effective for other diseases do not completely eradicate acne within a reasonable period of time. Even at the higher doses of anti-infectious chemotherapy used for more aggressive diseases, these anti-infectious agents do not completely clear acne.
I note here that acne appears to be more inflammatory than infectious, inflaming the face surround the pilosebaceous unit and only xe2x80x9cinfectingxe2x80x9d a single pilosebaceous unit. Acne is not characterized by a classic cellulitis that would assume to be migrating from the microabscess region. Rather, it develops a perilesional inflammatory reaction that persists and remains insidious until medical intervention occurs. If acne were indeed an xe2x80x9cinfectiousxe2x80x9d disease, left untreated we would expect it to spread to contiguous tissue creating a substantial problem. However, it never appears to do so.
In addition, the currently available treatments and management of acne and other inflammatory skin diseases using antibiotics appears to violate basic medical principles. Acne is a characterized as a microabscess. An abscess is typically treated by incision and drainage, not by antibiotics. Propionibacterium acnes (p. acnes) is an anaerobic diptheroid organism that does not appear to cause disease in any other areas of the human body. Thus, P. acnes should not be perceived as a primary pathogen but rather as an opportunist that becomes entrapped in the pilosebaceous unit. When entrapped, an anaerobic environment is created. This allows the bacteria to multiply, and pustie to form which eventually causes an inflammatory response in the individual. Certainly, when this occurs antibiotic treatment is useful to remove the growing bacteria and accounts for some of the limited success seen in patients treated with antibiotics.
What is needed is a treatment that is effective against all distinctive types of acne and a variety of other inflammatory skin diseases and is not laden with significant side effects.
Since the mid 1970""s medical research has emphasized and shown substantial evidence that a temporary excessive dihydrotestosterone production is implicated in the pathogenesis of acne vulgaris, androgenetic alopecia, idiopathic hirsutism and benign prostatic hypertrophy7. The studies by Sansoni and Mauvais-Jarvis clearly associate a local increase in dihydrotestosterone formation with the development of acne,7 and skin functions such as sebum secretions (Strauss and Pochi, 1963) and body hair growth are well known to be under androgen control4. The special article by Price in 1975 suggests that with the proper antiandrogen the highly desirable effect of reducing excessive dihydrotestosterone formation by blocking or selectively inhibiting testosterone 5 alpha reduction should have little systemic effect, and the psychological and other important roles of testosterone itself should not be affected7. Nonetheless, current therapy utilizing pharmacological agents that exhibit antiandrogenic activity have failed to live up to earlier expectations in the management of these diseases. For instance, the Type II 5 alpha reductase specific inhibitor Finasteride (Propecia), indicated for the treatment of androgenetic alopecia in men, is contraindicated in women and children and is associated with considerable precautions and adverse reactions such as two fold elevations in serum prostatic specific antigen and decreased labido, erectile dysfunction and ejaculatory dysfunction respectively6.
The following U.S. Patents are incorporated herein by reference: U.S. Pat. No. 6,034,228 Human signal transduction serine/threonine kinase, U.S. Pat. No. 6,034,057 Peptide inhibitors of fibronectin, U.S. Pat. No. 6,034,056 Fibronectin adhesion inhibitors, U.S. Pat. No. 6,008,223 Therapeutic compounds, U.S. Pat. No. 5,998,444 Piperidinyl compounds as NK1 or NK2 antagonists, U.S. Pat. No. 5,993,859 Pharmaceutical agents, U.S. Pat. No. 5,990,130 Therapeutic heterocycles, U.S. Pat. No. 5,977,135 Bicyclic heterocycles, U.S. Pat. No. 5,965,576 Cyclic amide derivatives for treating asthma, U.S. Pat. No. 5,965,396 Human lymph node derived GTPase, U.S. Pat. No. 5,962,265 Human signal transduction serine/threonine kinase, U.S. Pat. No. 5,900,432 Therapeutic N-(4-benzoyl-2-methyl-phenyl)-3,3,3-trifluoro-2-hydroxy-2-methyl-propanamides, U.S. Pat. No. 5,889,024 Substituted heterocycles, U.S. Pat. No. 5,866,568 Heterocyclic compounds, U.S. Pat. No. 5,861,401 N-heterocyclyl sulphonamide derivatives and their use as endothelin antagonists, U.S. Pat. No. 5,861,392 Therapeutic heterocycles, U.S. Pat. No. 5,739,149 Substituted piperidinobutyl nitrogen-containing heterocyclic compounds and analogues thereof as neurokinin antagonists, U.S. Pat. No. 5,731,309 Substituted heteroalkyleneamine neurokinin antagonists, U.S. Pat. No. 5,710,169 Therapeutic heterocycles, U.S. Pat. No. 5,705,505 Cyclic amide derivatives for treating asthma, U.S. Pat. No. 5,700,798 Methods for using benzoxazines for treating asthma, U.S. Pat. No. 5,693,639 Therapeutic heterocyclyl amionosulfonyl phenyl compounds, U.S. Pat. No. 5,677,317 Lactam compounds which are useful in the treatment of asthma, U.S. Pat. No. 5,668,137 N-heterocyclic sulfonamides having endothelin receptor activity, U.S. Pat. No. 5,654,299 Aryl substituted heterocycles, U.S. Pat. No. 5,641,793 Pyridine compounds which have useful pharmaceutical activity, U.S. Pat. No. 5,635,509 Piperidine derivatives useful as neurokinin antagonists, U.S. Pat. No. 5,622,964 Heterocyclic derivatives, U.S. Pat. No. 5,612,367 Method of enhancing bioavailability of pharmaceutical agents, U.S. Pat. No. 5,602,138 NKA affecting piperidyl heterobicyclic compounds, U.S. Pat. No. 5,589,489 Cyclic amide derivatives for treating asthma, U.S. Pat. No. 5,583,152 Method for treating vasospastic cardiovascular diseases heterocyclic amide derivatives, U.S. Pat. No. 5,576,333 Carboxamide derivatives, U.S. Pat. No. 5,567,700 Therapeutic heterocycles which antagonize neurokinin receptors, U.S. Pat. No. 5,559,132 Carboxamide derivatives for treating asthma, U.S. Pat. No. 5,559,131 Carboxamide derivatives for treating asthma, U.S. Pat. No. 5,534,525 Lactam derivatives, U.S. Pat. No. 5,521,199 Piperidinyl compounds as neurokinin receptor antagonists, U.S. Pat. No. 5,512,594 Ether derivatives having 5-lipoxygenase inhibitory activity, U.S. Pat. No. 5,510,386 Aminosulfonylphenyl compounds for treating urinary incontinence, U.S. Pat. No. 5,504,216 Method for repairing an amorphous sulfonamide, U.S. Pat. No. 5,504,089 2-hydroxyalkyl-benzimidazoles, -quinazolines and -benzothiazoles as potassium channel agonists, U.S. Pat. No. 5,486,515 2-fluoroalkyl-1,4-benzoxaxines as potassium channel mediators, U.S. Pat. No. 5,482,969 Certain N(4-benzoyl-2-phenyl)-3-trifluoro-2-hydroxy-propanamide derivatives, U.S. Pat. No. 5,482,966 Oxime derivatives, U.S. Pat. No. 5,482,963 Pharmaceutical agents useful as leukotriene antagonists, U.S. Pat. No. 5,478,843 Thiazole derivatives, U.S. Pat. No. 5,478,842 Ether derivatives having 5-lipoxygenase inhibitory activity, U.S. Pat. No. 5,457,125 Oxime derivatives, U.S. Pat. No. 5,455,253 Heterocyclic derivatives. U.S. Pat. No. 5,453,439 Hydroxylamine derivatives, U.S. Pat. No. 5,440,035 Heterocyclic amide derivatives, U.S. Pat. No. 5,420,298 Pyrrolidine derivatives, U.S. Pat. No. 5,411,973 Therapeutic alcohols, U.S. Pat. No. 5,401,751 Isoquinoline derivatives suitable for use in leukotriene mediated disease, U.S. Pat. No. 5,391,758 Heterocyclic amide derivatives, U.S. Pat. No. 5,376,680 Oxime derivatives, U.S. Pat. No. 5,373,007 Pyridooxazinyl or pyridothiazinyl as inhibitors of leukotrienes, U.S. Pat. No. 5,367,079 Cycloalkane derivatives, U.S. Pat. No. 5,350,754 Heterocyclic cycloalkanes, U.S. Pat. No. 5,338,734 Heterocyclic amide derivatives and pharmaceutical use thereof, U.S. Pat. No. 5,334,614 Hydroxylamine derivatives, U.S. Pat. No. 5,332,757 Oxime derivatives.
A method of treating acne and other inflammatory skin diseases is provided which comprises administering to a patient in need of treatment an anti-leukotriene or antihistamine agent, or other anti-inflammatory agent alone or in combination, preferably twice a day, preferably for at least two months.
Current treatment outcomes in patients with acne vulgaris are not consistent nor fully explained with present day therapy. Immunological factors appear to play a more important role than previously recognized. Because acne is an inflammatory skin disease, we investigated the use of anti-inflammatory agents on the treatment of acne. The anti-inflammatory agent we investigated most fully included the anti-leukotriene, zafirlukast.
With the onset of puberty and under the direction of androgenic hormones sebaceous glands enlarge secondary to increased triglyceride formation. Triglycerides are then hydrolyzed to free fatty acids by the enzyme hyaluronidase from p. acnes. With the release of hyaluronidase by p. acnes, hyaluronic acid present in cell coats breaks down. Free fatty acids are not truly immunogenic by themselves but become so by virtue of their chemical reactivity with self skin proteins thereby creating larger conjugates.4 Increasing complexity as well as host genetic factors contribute to a molecules immunogenicity. In the presence of this free fatty acid moiety, or immunogen, cell surface antibodies or immune system cells become reactive, triggering the release of leukotrienes, histamines, and other vasoactive substances. Tissue congestion occurs compromising the orifice of the pilosebaceous complex ultimately creating an impaction at the follicle. The microcomedo, or acne precursor lesion, is the resultant product of this process. Extravasation of the contents of the pilosebaceous unit into the surrounding dermis results in the inflammatory acne lesion. Eventually, follicle walls rupture and acne nodules develop. Supportation of the acne nodule results in the acne cyst.
Because the inflammatory response of the acne lesion is mediated by the release of leukotrienes, and histamines, then the introduction of anti-leukotrienes and/or antihistamines will effectively prevent the formation of new acne lesions and exert a significant impact on the resolution of old lesions.
Anti-leukotrienes are a topic of great interest at the present time. Leukotriene (LT) synthesis begins with phospholipase A2 mediated conversion of phosphatidyl choline from the nuclear membrane to arachidonic acid. Arachidonic acid binds to 5-lipoxygenase (5-LO) activating protein (FLAP) effectively increasing its concentration in the vicinity of the 5-LO enzyme. Arachidonic acid is then converted to leukotriene A4 (LTA4). LTA4 may then be converted to the chemotaxin LTB4, or, in sequential steps to LTC4, LTD4, and LTE4, LTC4, LTD4, and LTE4 are the cysteinyl leukotrienes.
There are two types of anti-leukotriene agents, LT synthesis inhibitors and LT receptor antagonists. Zafirlukast is an anti-leukotriene that competitively inhibits the binding of leukotriene D4 at its receptor site. Currently, the medical applications of zafirlukast is in the prophylactic treatment of patients with mild to moderate asthma.5 Zafirlukast alone has already become established as the standard of care in long term asthma management in both adolescence and adults, and is now indicated for use in the pediatric population aged seven and above. Results of other studies suggest efficacy in the treatment of leprosy reaction,14 migraine prophylaxis11, atopic dermatitis2 and chronic urticaria.12 
It is important to note that zafirlukast (such as Accolate(copyright)) is a selective and competitive receptor antagonist of leukotriene D4 and E4 components of slow reactive substances of anaphylaxis. Zafirlukast is a member of a class of drugs initially called the LTD4-receptor-antagonists. These drugs are now named the CysLT1-antagonists to xe2x80x9crecognize that each of LTC4, LTD4 or LTE4 is a potential natural agonist at their common receptor in human airwaysxe2x80x9d9. Zafirlukast inhibits leukotriene formation by competitively inhibiting the binding of leukotriene D4 at its receptor site; it does not inhibit the formation of leukotriene B4. Because leukotriene B4 is relatively high up in the cascade of events leading to the synthesis of the cysteinyl leukotrienes (LTC4, LTD4, and LTE4), blocking leukotriene B4 formation can cause more general and significant deleterious side effects not seen by more specific targeting of the downstream leukotrienes LTC4, LTD4, and LTE4 as is the case with zafirlukast.